Letter pubs.acs.org/OrgLett
Efficient and Practical Oxidative Bromination and Iodination of Arenes and Heteroarenes with DMSO and Hydrogen Halide: A Mild Protocol for Late-Stage Functionalization Song Song,† Xiang Sun,† Xinwei Li,† Yizhi Yuan,† and Ning Jiao*,†,‡ †
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing 100191, China ‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China S Supporting Information *
ABSTRACT: An efficient and practical system for inexpensive bromination and iodination of arenes as well as heteroarenes by using readily available dimethyl sulfoxide (DMSO) and HX (X = Br, I) reagents is reported. This mild oxidative system demonstrates a versatile protocol for the synthesis of aryl halides. HX (X = Br, I) are employed as halogenating reagents when combined with DMSO which participates in the present chemistry as a mild and inexpensive oxidant. This oxidative system is amenable to late-stage bromination of natural products. The kilogram-scale experiment (>95% yield) shows great potential for industrial application.
A
are not good choices for large scale halogenations because of the expensive price and the generation of organic wastes. Hydrogen halides (HX), the byproduct of X2-based halogenations, are readily available, inexpensive, and easy to store and transport. Inspired by the enzyme-catalyzed oxidative halogenation in nature,5 various oxidative halogenations consisting of generating the halogenating reagent in situ from halide are reported in the literature,6 where residual HX is oxidized by the oxidants such as selectfluor, persulfates, hypervalent iodine, molecular oxygen, hydrogen peroxide, etc. However, limited substrate scope, low atom economy, poor regioselectivity, or the potential explosivity of oxidants substantially restricts the utility of these oxidative halogenations. Importantly, the reported oxidative systems show limitations in halogenation of heteroarenes.6 Dimethyl sulfoxide (DMSO), which is industrially produced by oxidation of dimethyl sulfide with nitrogen dioxide or oxygen,7 is utilized as the oxygen,8 carbon,9 or sulfur10 source in many reactions. The combination of DMSO and HBr has been used in the bromination of arenes (Scheme 1b, eq 2).11 However, the reported reactions suffered from several drawbacks (Scheme 1b): (1) The bromination of heteroarenes with DMSO/HBr has not been reported except for pyrrole derivatives; (2) the iodination of arenes cannot be achieved by their strategies; (3) the dibromination was uncontrollable due to the use of >9 equiv of HBr (thus, the bromination of electron-rich arenes such as m-dimethoxybenzene mainly afforded the dibrominated product); (4) a less than 40% yield was obtained when 2 equiv of HBr were employed. The
ryl halides are among the most common and important chemicals1 and are present in many natural products.2 The current dominant industrial approach to aryl bromides and iodides is the halogenation of arenes with X2 (X = Br, I) which suffers from obvious limitations (Scheme 1a): (1) X2 are Scheme 1. Bromination and Iodination of Arenes
hazardous, toxic, and corrosive reagents; (2) Halide-atom economy is below 50% with HX as the byproduct; (3) Sometimes, the undesirable byproducts are uncontrollable. To avoid the use of X2, some modified reagents such as Nhalosuccinimides (NBS or NIS) and their analogues which are operationally safe in comparison with that of X2 and do not produce HX, have been developed.3,4 However, these reagents © 2015 American Chemical Society
Received: March 31, 2015 Published: May 26, 2015 2886
DOI: 10.1021/acs.orglett.5b00932 Org. Lett. 2015, 17, 2886−2889
Letter
Organic Letters Scheme 3. DMSO/HBr for Bromination of Arenesa
above-mentioned limitations are why this reaction rarely has been used in organic synthesis. According to Yoshida’s report, the halide cation would form X+(DMSO)n in the presence of DMSO (Scheme 1c, eq 3).12 We hypothesized that the excess DMSO strongly reduced the reactivity of X+ generated from DMSO/HX in Majetich’s report.11a Therefore, we speculated that the efficient halogenation of arenes with stoichiometric HX would be possible if stoichiometric DMSO was used as the oxidant instead of as the solvent. Herein, we describe the simple and practical bromination and iodination of arenes as well as various heteroarenes with stoichiometric aqueous HX (X = Br, I) and DMSO performed in EtOAc (Scheme 1d, eq 4). The high halide-atom economy, broad substrate scope, easy accessibility, and low cost of aqueous HX and DMSO make this strategy extremely attractive in the development of efficient approaches to aryl bromides and iodides. The mild and simple conditions are amenable to late-stage functionalization of natural products. Initially, we chose m-dimethoxybenzene 1a as the substrate, from which the bromination afforded mono- and dibrominated products in Majetich’s report (Scheme 1b, eq 2).11a The bromination of 1a with 1.1 equiv of HBr in DMSO as solvent at 35 °C afforded 2a in only 34% (for 1 h) and 49% yield (for 24 h), respectively (Scheme 2, eq 5), which were in accordance
a
The solution of 1 (0.5 mmol), DMSO (0.55 mmol), and HBr (48%) in EtOAc (2 mL) was stirred under air at 60 °C. For 1a−k, 1.1 equiv of HBr was used. For 1m−u, 2.2 equiv of HBr were used. Isolated yields. bWith 4 equiv of DMSO and HBr. cWith 8 equiv of DMSO and HBr in AcOH (2 mL). dWith 1.05 equiv of DMSO and HBr.
Scheme 2. Bromination of m-Dimethoxybenzene
Furthermore, the 1.0 kg scale bromination of 1g with a 96% yield shows great potential for industrial applications of this low-cost protocol (Scheme 3). Heteroaromatic halogenations are very important because they are ubiquitous in modern medicinal chemistry.15 Therefore, the development of new approaches to heteroaromatic halides has always drawn chemists’ attention.16 Very recently, Glorius and co-workers reported the Rh-catalyzed regioselective halogenation of heterocycles.16a The chlorination of heteroarenes was realized by using Palau’chlor developed by Baran.16b We then investigated the heteroaromatic brominations with the present DMSO/HBr system (Scheme 4). Indole compounds 3a−k were brominated in excellent yields within an hour. It is noteworthy that the oxidative bromination of indole compounds without the protecting group on the nitrogen atom could not be achieved using other oxidants such as O26c or selectfluor.6i Other heteroarenes including 7-azaindole 3l, indazole 3m, pyrazoles 3n−o, pyrimidazole 3p, 1,7-diazaindolizine 3q, thiophene 3r, benzothiophene 3s, and benzofuran 3t could all be regioselectively brominated in good yields. The bromide substituent can greatly change the drugs’ or natural products’ properties.17 We tried to expand our simple and mild method to the direct bromination of natural or bioactive compounds (Scheme 5). The selective bromination of δ-tocopherol 5a with Br2 was a challenge and showed poor regioselectivity even at very low temperature.18 Gratifyingly, the bromination of 5a with the DMSO/HBr system afforded monobrominated product 6a as the sole product in 94% yield. Xanthotoxin 5b was brominated in high yield without affecting the furan or lactone group. The bromination of two alkaloid natural products19 esermethole 5c and desoxyeseroline 5d proceeded smoothly to afford monobrominated alkaloids 6c−d in high yields. Sinomenine 5e was brominated in 75% yield tolerating ketone, amino, and alkene groups. Furthermore,
with Majetich’s report11a (Scheme 1b) and proved that the reactivity of Br+ in DMSO was very low. To our delight, with 1.1 equiv of DMSO and aqueous HBr (48%) in EtOAc at 35 °C for 1 h, 2a was obtained as the sole product in 90% yield (Scheme 2, eq 6). The bromination of 1a proceeded rapidly (15 min) to afford 2a in 94% yield at 60 °C (Scheme 3). Under these conditions, arenes 1b−k bearing methoxy or hydroxy substituents were monobrominated in high to excellent yields with selectivity that at first approximation parallels Friedel−Crafts reactivity (Scheme 3). The bromination of some electron-rich substrates 1c, 1h, 1j, and 1k performed very rapidly (10−15 min) in high yields. Vanilli 1i was brominated in 96% yield and the aldehyde group, which is easily oxidized under oxidative conditions, was retained.13 Notably, 2,2′-Binol 1l was dibrominated smoothly in 89% yield. This efficient system could cover the aniline derivatives (1m−u, Scheme 3). A series of primary 1m−p, secondary 1q− r, and tertiary amines 1s−u were monobrominated in high yields with 1.1 equiv of DMSO and 2.2 equiv of HBr. Notably, the bromination of substrates 1q, 1s, and 1u with unsubstituted ortho and para positions gave para-brominated products. Furthermore, the bromination at the benzyl position, which usually happened in other oxidative processes,14 was not detected in the present system. The electron-poor arenes such as benzoic acid, nitrobenzene, or benzonitrile did not work in the present DMSO/HBr system. 2887
DOI: 10.1021/acs.orglett.5b00932 Org. Lett. 2015, 17, 2886−2889
Letter
Organic Letters Scheme 4. DMSO/HBr for Bromination of Heteroarenesa
equiv of DMSO in EtOAc at 60 °C (see Supporting Information). Under the optimized conditions, a series of arenes were iodinated successfully (Scheme 7). The iodination Scheme 7. DMSO/NH4I for Iodination of Arenesa
a
The solution of 3 (0.5 mmol), DMSO (0.6 mmol), and HBr (48%, 0.6 mmol) in EtOAc (2 mL) was stirred under air at 60 °C. Isolated yield. bWith 1.5 equiv of DMSO and HBr. cWith 1.5 equiv of DMSO and 2.5 equiv of HBr. dWith 4 equiv of DMSO and HBr.
Scheme 5. DMSO/HBr for Bromination of Natural Productsa
a
The solution of arene, DMSO, NH4I (y equiv), and H2SO4 in EtOAc was stirred under air at 60 °C. b80 °C. cy = 3, 80 °C. dy = 2, 80 °C. ey = 2, 80 °C, 3.5 equiv of H2SO4.
of anisole derivatives performed well to afford 7b−e in high yields. Phenol derivatives bearing methyl 7f, 7i−l, benzyl 7g, phenyl 7h, or iodo 7l substituents were iodinated in good to high yields. Heteroaromatic iodides including thiophene 7m, benzothiophene 7n, indole 7o, 7-azaindole 7p, and pyrazole 7q were also synthesized by the present DMSO/HI system. The gram-scale synthesis of 1-iodo-2-naphthol 7a (16.1 g) was also achieved in 86% yield. Notably, the mono- and dihalogenation could be efficiently controlled by only adjusting the dosage of HX (X = Br, I) and DMSO (Scheme 8). For example, diiodinated or dibrominated
a
The solution of 5, DMSO (1.1 equiv), and aquesous HBr in EtOAc was stirred under air at 60 °C. bWith 1.1 equiv of HBr. cWith 3 equiv of DMSO and HBr. dWith 3 equiv of HBr. eWith 2.2 equiv of HBr in CHCl3/EtOAc (1:3). fWith 8 equiv of DMSO and HBr.
Scheme 8. DMSO/HX for Dihalogenation of Arenes
exposure of calix[4]arene 5f to 8 equiv of DMSO and HBr in EtOAc afforded the desired tetrabrominated product 6f in 82% yield. These brominations indicate that the DMSO/HBr system is amenable to late-stage functionalization of natural products and show high potential applications in biological evaluation. Majetich and co-workers investigated the iodination of arenes with HI in DMSO; however, no aryl iodides were obtained.11a Inspired by the above bromination reaction, we expected that if stoichiometric DMSO was used as the oxidant, the iodination of arenes would be possible. As expected, with 1.5 equiv of HI and DMSO in EtOAc at 60 °C, the iodination of 2-naphthol afforded 7a in 67% yield (Scheme 6). After extensively screening parameters of the reaction conditions, we were delighted to find that the best yield was obtained with 1.2 equiv of NH4I, 1.8 equiv of H2SO4, and 3.6
arenes 8 were obtained in high yields with 2 equiv of HX. Compared to the previous reports on the adjustment of monoand dihalogenation by the reaction time or reaction temperature,6c,11 the present strategy shows higher selectivity. According to previous research,20 [Br+DMS]Br− would be generated in situ from DMSO and HBr.21 Based on previous reports and our experimental results, we proposed the mechanism of halogenations with DMSO/HX (Scheme 9). We thought that the HX was oxidized by DMSO to X2 or DMS·X2. The reaction of X2 or DMS·X2 with arene afforded the aryl halides with the formation of HX which was oxidized by DMSO for the next oxidative cycle. Thus, stoichiometric DMSO and HX is sufficient for full conversion of the arenes. The slow generation of X2 in situ is crucial for highly regioselective halogenation of arenes in our strategy.
Scheme 6. Iodination of 2-Naphthol
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Organic Letters
Soc. 2006, 128, 7416. (p) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (5) Vaillancourt, F. H.; Yeh, E.; Vosburg, D. A.; Garneau-Tsodikova, S.; Walsh, C. T. Chem. Rev. 2006, 106, 3364. (6) For related oxidative halogenations, see: (a) Podgoršek, A.; Zupan, M.; Iskra, J. Angew. Chem., Int. Ed. 2009, 48, 8424. (b) Yonehara, K.; Kamata, K.; Yamaguchi, K.; Mizuno, N. Chem. Commun. 2011, 47, 1692. (c) Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 45, 6460. (d) Sels, B. F.; De Vos, D. E.; Jacobs, P. A. J. Am. Chem. Soc. 2001, 123, 8350. (e) Shi, L.; Zhang, D.; Lin, R.; Zhang, C.; Li, X.; Jiao, N. Tetrahedron Lett. 2014, 55, 2243. (f) Wang, G.-W.; Gao, J. Green Chem. 2012, 14, 1125. (g) Pandit, P. K.; Gayen, S.; Khamarui, S.; Chatterjee, N.; Maiti, D. K. Chem. Commun. 2011, 47, 6933. (h) Dewkar, G. K.; Narina, S. V.; Sudalai, A. Org. Lett. 2003, 5, 4501. (i) Bedrač, L.; Iskra, J. Adv. Synth. Catal. 2013, 355, 1243. (7) Roy, K.-M., Ed. Sulfones and Sulfoxides in Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, 2002. (8) (a) Song, S.; Huang, X.; Liang, Y.-F.; Yuan, Y.; Li, X.; Jiao, N. Green Chem. 2015, 17, 2727. (b) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2014, 53, 7144. (c) Mupparapu, N.; Khan, S.; Battula, S.; Kushwaha, M.; Gupta, A. P.; Ahmed, Q. N.; Vishwakarma, R. A. Org. Lett. 2014, 16, 1152. (d) Wu, X.; Gao, Q.; Liu, S.; Wu, A. Org. Lett. 2014, 16, 2888. (e) Gao, Q.; Wu, X.; Liu, S.; Wu, A. Org. Lett. 2014, 16, 1732. (f) Ashikari, Y.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2011, 133, 11840. (g) Ashikari, Y.; Nokami, T.; Yoshida, J. Org. Lett. 2012, 14, 938. (h) Xu, R.; Wan, J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132, 15531. (9) (a) Jiang, X.; Wang, C.; Wei, Y.; Xue, D.; Liu, Z.; Xiao, J. Chem.Eur. J. 2014, 20, 58. (b) Qian, J.; Zhang, Z.; Liu, Q.; Liu, T.; Zhang, G. Adv. Synth. Catal. 2014, 356, 3119. (c) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47, 6725. (d) Lv, Y.; Li, Y.; Xiong, T.; Pu, W.; Zhang, H.; Sun, K.; Liu, Q.; Zhang, Q. Chem. Commun. 2013, 49, 6439. (10) (a) Liu, F.-L.; Chen, J.-R.; Zou, Y.-Q.; Wei, Q.; Xiao, W.-J. Org. Lett. 2014, 16, 3768. (b) Mal, K.; Sharma, A.; Maulik, P. R.; Das, I. Chem.Eur. J. 2014, 20, 662. (c) Gao, Q.; Wu, X.; Li, Y.; Liu, S.; Meng, X.; Wu, A. Adv. Synth. Catal. 2014, 356, 2924. (d) Chu, L.; Yue, X.; Qing, F.-L. Org. Lett. 2010, 12, 1644. (e) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Org. Lett. 2006, 8, 2245. (f) Hu, G.; Xu, J.; Li, P. Org. Lett. 2014, 16, 6036. (g) Gao, X.; Pan, X.; Gao, J.; Huang, H.; Yuan, G.; Li, Y. Chem. Commun. 2015, 51, 210. (h) Jiang, Y.; Loh, T.P. Chem. Sci. 2014, 5, 4939. (11) (a) Majetich, G.; Hicks, R.; Reister, S. J. Org. Chem. 1997, 62, 4321. (b) Liu, C.; Dai, R.; Yao, G.; Deng, Y. J. Chem. Res. 2014, 38, 593. (12) Ashikari, Y.; Shimizu, A.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2013, 135, 16070. (13) Hassall, C. H. Org. React. 1957, 9, 73. (14) Mestres, R.; Palenzuela, J. Green Chem. 2002, 4, 314. (15) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. (16) (a) Schröder, N.; Lied, F.; Glorius, F. J. Am. Chem. Soc. 2015, 137, 1448. (b) Rodriguez, R. A.; Pan, C.-M.; Yabe, Y.; Kawamata, Y.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 6908. (17) Bunders, C. A.; Minvielle, M. J.; Worthington, R. J.; Ortiz, M.; Cavanagh, J.; Melander, C. J. Am. Chem. Soc. 2011, 133, 20160. (18) Patel, A.; Böhmdorfer, S.; Hofinger, A.; Netscher, T.; Rosenau, T. Eur. J. Org. Chem. 2009, 4873. (19) Zhan, F.; Liang, G. Angew. Chem., Int. Ed. 2013, 52, 1266. (20) (a) Mislow, K.; Simmons, T.; Melillo, J.; Ternay, A. J. Am. Chem. Soc. 1964, 86, 1452. (b) Floyd, M.; Du, M.; Fabio, P.; Jacob, L.; Johnson, B. J. Org. Chem. 1984, 50, 5022. (21) Choudhury, L. H.; Parvin, T.; Khan, A. T. Tetrahedron 2009, 65, 9513.
Scheme 9. Proposal Mechanism
In conclusion, we have demonstrated an efficient and practical oxidative DMSO/HX system for the halogenation of arenes and heteroarenes. This mild oxidative system is effective as a versatile protocol for the synthesis of aryl halides and a mild method for late-stage modification of natural products. Efforts to expand this DMSO/HX system to other reactions are continuing.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, full characterization of products, and copies of NMR spectra. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.5b00932.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Basic Research Program of China (973 Program) (grant No. 2015CB856600), National Natural Science Foundation of China (Nos. 21325206, 21172006), and National Young Top-notch Talent Support Program are greatly appreciated. We also thank Guangxin Liang at NKU and Yanxing Jia at PKU for natural products donation. We thank Xiaoqiang Huang in this group for reproducing the results of 4l, 4n, and 6a.
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REFERENCES
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DOI: 10.1021/acs.orglett.5b00932 Org. Lett. 2015, 17, 2886−2889
